Fused pyridazine derivatives as nlrp3 inhibitors

Abstract

Disclosed are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein α, β, m, R5, R6, R7, R8, R9, R10, R11, Ra,Rb, X1, X2, X3, X4 and X8 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula (I), to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with NLRP3.

What is claimed is: 
     
         1 . A compound of Formula 1, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof in which: 
         a is a single bond and p is a single bond; and
 X 1  is CH 2 ; 
 X 2  is O and X 3  is CH 2 , or 
 X 2  is CH 2  and X 3  is O; and 
 X 4  is CH 2 ; 
 
         m is selected from 0, 1 and 2; 
         each R a  and R b  is independently selected from hydrogen and C 1-4  alkyl, or R a  and R b , together with a carbon atom to which both R a  and R b  are attached, form a C 3-6  cycloalkylidene, provided if m is 2, then no more than one R a  and R b , together with the carbon atom to which R a  and R b  are attached, form a C 3-6  cycloalkylidene; 
         R 5  is selected from:
 (a) C 3-8  cycloalkyl, which is substituted with 0 to 5 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo; 
 (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and 
 (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo; 
 
 provided:
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy and R 9  is CF 3  or OCF 3 , then R 5  is not 3-hydroxy-3-methylcyclobutyl; 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy and R 9  is CF 3  or OCF 3 , then R 5  is not 3-hydroxy-3-methylcyclobutyl; 
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy, and R 9  is hydrogen, CF 3 , OCF 3  or cyclobutyl, then R 5  is not 2-hydroxycyclohexyl; 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy, and R 9  is hydrogen, chloro, CF 3 , CHF 2 , OCF 3 , OCHF 2 , OCH 3  or cyclobutyl, then R 5  is not 2-hydroxycyclohexyl; 
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6  and R 10  are each hydrogen, R 7  is hydroxy, R 9  is methyl, and R 11  is fluoro, then R 5  is not 2-hydroxycyclohexyl; 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6  and R 10  are each hydrogen, R 7  is hydroxy, R 9  is methyl, and R 11  is fluoro, then R 5  is not 2-hydroxycyclohexyl; 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6  and R 11  are each hydrogen, R 7  is hydroxy, R 9  is CF 3 , and R 10  is fluoro, then R 5  is not 2-hydroxycyclohexyl; 
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy, and R 9  is CF 3 , then R 5  is not 2-cyanocyclohexyl or 2-aminocyclohexyl; and 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy, and R 9  is CF 3 , then R 5  is not 2-cyanocyclohexyl; 
 
 (b) C 3-8  heterocyclyl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo; 
 (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and 
 (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo; 
 
 and in which a nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:
 (i) C 1-4  alkyl, C1.4 alkylcarbonyl and C 1-4  alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; 
 (ii) C 3-8  cycloalkyl-(CH 2 ) n , which C 3-8  cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, C 1 0.4 alkyl, C 1-4  alkylcarbonyl, C 1-4  alkoxy and oxo; and 
 (iii) phenyl-(CH 2 ) n  and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1 0.4 alkyl and C 1 0.4 alkoxy; 
 
 wherein the C 3-8  heterocyclyl has only one ring heteroatom, the ring heteroatom being selected from nitrogen, oxygen, and sulfur; and 
 n is selected from 0 and 1; 
 provided:
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy and R 9  is CF 3 , then R 5  is not piperidin-3-yl or 1-methylpiperidin-3-yl; 
 if m is 0, X 1 , X 3  and X 4  are each CH 2 , X 2  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy and R 9  is CF 3 , then R 5  is not piperidin-3-yl or 1-methylpiperidin-3-yl; 
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6  and R 10  are each hydrogen, R 7  is hydroxy, R 9  is CF 3 , methyl or chloro, and R 11  is fluoro, then R 5  is not 1-methylpiperidin-3-yl; and 
 if m is 0, X 1 , X 2  and X 4  are each CH 2 , X 3  is 0, X 8  is CH, R 6 , R 10  and R 11  are each hydrogen, R 7  is hydroxy and R 9  is methyl or chloro, then R 5  is not 1-methylpiperidin-3-yl; 
 
 (c) phenyl, which is substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4  alkyl and C 1-4  alkoxy, provided at least one of the substituents is hydroxy; 
 
         R 6  is selected from hydrogen and C 1-4  alkyl; 
         X 8  is selected from N and CR 8 ; 
         R 7 , R 8  and R 11  are each independently selected from:
 (i) hydrogen, halo, hydroxy and cyano; 
 (ii) C 1-4  alkyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and 
 (iii) C 3-8  cycloalkyl which is substituted with 0 to 3 substituents independently selected from halo, C 1-4  alkyl and C 1 0.4 alkoxy; and 
 
         R 9  and R 10  are each independently selected from:
 (i) hydrogen, halo, hydroxy and cyano; 
 (ii) C 1-4  alkyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo; and 
 (iii) C 3-8  cycloalkyl which is substituted with 0 to 3 substituents independently selected from halo, C 1-4  alkyl and C 1-4  alkoxy; or 
 
         R 9  and R 10  form an ethan-1,2-dioxy moiety bridging the carbon atoms to which they are attached. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein X 2  is O and X 3  is CH 2 . 
     
     
         3 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 2 , wherein m is 0. 
     
     
         4 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 2 , wherein m is 1 or 2. 
     
     
         5 . The compound or pharmaceutically acceptable salt according to  claim 4 , wherein each R a  and R b  is independently selected from hydrogen and C 1-4  alkyl. 
     
     
         6 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  cycloalkyl, which is substituted with 0 to 5 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and   (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo.   
     
     
         7 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is a cycloalkyl which is selected from cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-1-yl, each substituted with 0 to 5 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and   (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo.   
     
     
         8 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  heterocyclyl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and   (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo;   
       and in which a nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:
 (i) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; 
 (ii) C 3-8  cycloalkyl-(CH 2 ) n , which C 3-8  cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, C 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkoxy and oxo; and 
 (iii) phenyl-(CH 2 ) n  and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4  alkyl and C 1-4  alkoxy. 
 
     
     
         9 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  heterocyclyl in which the ring heteroatom is nitrogen and up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and   (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo;   
       and in which the nitrogen ring atom is unsubstituted or substituted with a substituent selected from:
 (i) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; 
 (ii) C 3-8  cycloalkyl-(CH 2 ) n , which C 3-8  cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, C 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkoxy and oxo; and 
 (iii) phenyl-(CH 2 ) n  and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4  alkyl and C 1-4  alkoxy. 
 
     
     
         10 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  heterocyclyl which is selected from piperidin-3-yl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:
 (i) halo, hydroxy, cyano and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from C 1-4  alkyl; and   (iii) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkoxy, each substituted with 0 to 3 substituents independently selected from halo;   
       and in which the nitrogen ring atom of the piperidin-3-yl is unsubstituted or substituted with a substituent selected from:
 (i) C 1-4  alkyl, C 1-4  alkylcarbonyl and C 1-4  alkylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; 
 (ii) C 3-8  cycloalkyl-(CH 2 ) n , which C 3-8  cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, C 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkoxy and oxo; and 
 (iii) phenyl-(CH 2 ) n  and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4  alkyl and C 1-4  alkoxy. 
 
     
     
         11 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  heterocyclyl which is selected from piperidin-3-yl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:
 (i) halo and oxo;   (ii) amino, which is substituted with 0 to 2 substituents independently selected from methyl; and   (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from fluoro;   
       and in which the nitrogen ring atom of the piperidin-3-yl is unsubstituted or substituted with a substituent selected from:
 (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each substituted with 0 to 3 substituents selected from fluoro; 
 (ii) C 3-5  cycloalkyl-(CH 2 ) n , which C 3-5  cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from methyl and methoxy; and 
 (iii) phenyl-(CH 2 ) n  and pyridinyl-(CH 2 ) n , which phenyl and pyridinyl moieties are unsubstituted. 
 
     
     
         12 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is C 3-8  heterocyclyl which is selected from piperidin-3-yl in which up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from halo, oxo, methyl, ethyl, propyl and isopropyl, and in which the nitrogen ring atom of the piperidin-3-yl is unsubstituted or substituted with a substituent selected from methyl, ethyl, isopropyl and C 3-5  cycloalkyl-(CH 2 ) n . 
     
     
         13 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 12 , wherein R 5  is C 3-8  heterocyclyl in which at least one of the carbon ring atoms of the R 5  heterocyclyl is substituted. 
     
     
         14 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 12 , wherein R 5  is C 3-8  heterocyclyl in which at least one of the carbon ring atoms of the R 5  heterocyclyl is substituted with halo 
     
     
         15 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 12 , wherein R 5  is C 3-8  heterocyclyl in which at least one of the carbon ring atoms of the R 5  heterocyclyl is substituted with fluoro. 
     
     
         16 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 15 , wherein R 5  is C 3-8  heterocyclyl in which a nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from methyl, ethyl, isopropyl and C 3 0.5 cycloalkyl-(CH 2 ) n . 
     
     
         17 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 15 , wherein R 5  is C 3-8  heterocyclyl in which a nitrogen ring atom, if present, is substituted with a substituent selected from methyl, ethyl, isopropyl and C 3-5  cycloalkyl-(CH 2 ) n . 
     
     
         18 . The compound or pharmaceutically acceptable salt according to any one of  claims 8 to 17 , wherein R 5  is C 3-8  heterocyclyl and n is 0. 
     
     
         19 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 5 , wherein R 5  is phenyl, which is substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4  alkyl and C 1-4  alkoxy, provided at least one of the substituents is hydroxy. 
     
     
         20 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 19 , wherein R 6  is selected from hydrogen and methyl. 
     
     
         21 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 19 , wherein R 6  is hydrogen. 
     
     
         22 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 21 , wherein X 8  is CR 8 . 
     
     
         23 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 22 , wherein R 8  and R 11  are both hydrogen, and R 7  is selected from:
 (i) hydrogen, halo and hydroxy; and   (ii) C 1-3  alkyl and C 1-3  alkoxy, each substituted with 0 to 3 substituents independently selected from halo.   
     
     
         24 . The compound or pharmaceutically acceptable salt according to any one of  claims 1 to 23 , wherein R 9  and R 10  are each independently selected from:
 (i) hydrogen, halo, hydroxy and cyano;   (ii) C 1-4  alkyl and C 1-3  alkoxy, each substituted with 0 to 3 fluoro; and   (iii) C 3-5  cycloalkyl which is substituted with 0 to 3 substituents independently selected from methyl and methoxy.   
     
     
         25 . The compound according to  claim 1 , which is selected from the following compounds:
 5-chloro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol;   2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-methylphenol;   2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol;   5-fluoro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol;   1-(2-(difluoromethyl)-4-methylphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   1-(2-(difluoromethyl)-4-methoxyphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   4-(2-(difluoromethyl)-4-methylphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   4-(2-(difluoromethyl)-4-methoxyphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4-(2-fluoro-4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4-(4-methoxy-2-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   4-(4-chloro-2-fluorophenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   5-chloro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4-(2-fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1-(2-fluoro-4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1-(4-methoxy-2-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   1-(4-chloro-2-fluorophenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   (R)-5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   5-fluoro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol;   (R)-5-methoxy-2-(4-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   (R)-1-(4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   (R)-4-(4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine;   (R)-5-chloro-2-(4-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   (R)-2-(4-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   (R)-2-(1-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol;   (R)—N-(1-cyclopropylpiperidin-3-yl)-1-(4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine;   2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol;   2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-methylphenol;   4-((1-(2-hydroxy-4-methylphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino)bicyclo[2.2.1]heptan-1-ol;   4-((4-(2-hydroxy-4-methylphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino)bicyclo[2.2.1]heptan-1-ol;   (R)-2-(4-((1-(2-methoxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol;   2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;   2-(4-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol;   2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol;   2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methoxyphenol;   5-cyclopropyl-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol;   5-(difluoromethyl)-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; and   a pharmaceutically acceptable salt of any one of the aforementioned compounds.   
     
     
         26 . A compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25  for use as a medicament. 
     
     
         27 . A pharmaceutical composition comprising:
 a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 ; and   a pharmaceutically acceptable excipient.   
     
     
         28 . A compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25  for use in treating a disease, disorder or condition associated with NLRP3. 
     
     
         29 . A compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25  for use in treating a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene. 
     
     
         30 . A compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25  for use in treating a cryopyrin-associated periodic syndrome (CAPS). 
     
     
         31 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 , wherein the disease, disorder or condition is associated with NLRP3. 
     
     
         32 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 , wherein the disease, disorder or condition is associated with a heterozygous gain of function mutation in the NLRP3 gene. 
     
     
         33 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 , wherein the disease, disorder or condition is cryopyrin-associated periodic syndrome (CAPS). 
     
     
         34 . The method according to  claim 33 , wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID/CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS). 
     
     
         35 . A method of treating a neurodegenerative disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 . 
     
     
         36 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 , wherein the disease, disorder or condition is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and prion disease. 
     
     
         37 . A combination comprising a compound or pharmaceutically acceptable salt as defined in any one of  claims 1 to 25 , and at least one additional pharmacologically active agent. 
     
     
         38 . The combination according to  claim 37 , wherein the additional pharmacologically active agent is selected from beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.